Abstract/Project Summary: Most colorectal cancers (CRCs) arise from adenomatous precursors. Accumulated oncogene and tumor suppressor gene (TSG) defects have been argued to underlie adenoma development and progression of some lesions to carcinoma. Gene defects with key roles in tumor initiation, progression, and maintenance are termed "drivers". In contrast, a "passenger" defect might simply have arisen coincident with a driver alteration. Recent studies in CRC show that whereas the APC (adenomatous polyposis coli), KRAS, and p53 genes are each frequently altered, many other genes are each mutated in only a subset of CRCs. Thus, sorting out driver and passenger defects may be challenging and will likely require in-depth work. The overarching objective of the proposal is to define the functional contribution of selected recurrent gene defects in CRC by employing genetically engineered mouse models where specific genes are somatically targeted in mouse colon epithelium using CDX2P-Cre transgenes. The specific aims are: I) Establish that Cdx2 functions as a "gatekeeper" in inhibiting adenoma formation and that bi-allelic Cdx2 defects promote adenoma development via mechanisms distinct from those linked to Apc inactivation;II) Define if and how somatic p53 missense mutations, but not p53 null mutations, promote colorectal adenoma- carcinoma progression;and III) Based on somatic mutations in the gene encoding the DNA repair and genomic stability protein MRE11 in human CRCs, determine if the mouse Mre11 gene functions as a TSG in adenoma-carcinoma progression and, if so, whether Mre11 inactivation promotes genomic instability in tumors. While each aim focuses on a different gene and its potential role in colorectal tumorigenesis, the aims are united by commonalities in approach and the goal of testing key concepts in CRC, such as the identity of gatekeeper genes and how multiple defects collaborate in tumorigenesis. The colon tumor models also represent a new direction, as small intestinal tumor models have dominated work in the field to date.